Gulf War Illness Research

Go to page

Senior Member

"What Dr. Watkins suspects, based on her research on microglia in chronic pain, is that an initial exposure to some toxin "primes" the microglia in the brain to make them hyper alert. Then when a second infection, injury, or toxin is experienced, the brain's immune cells over-react, releasing too much of the chemical signals that cause the "sickness response", and they do not stop releasing the substances after the body heals. In the case of Gulf War veterans, the "initial trigger" could have been a reaction to an immunization, stress, or exposure to low-level toxins. Later a second insult to the body unleashes a run-away illness. Research from several labs on microglia in chronic pain has identified many steps in this neuro-immune signaling process that become disrupted and researchers have found specific drugs to restore the normal function of these pain circuits, thus ending the chronic pain. Most of this work is in laboratory animals but clinical studies are now under way."

Senior Member

Thanks Frickly! For a quick look, here is the entire article.
I wonder if this might be related to Dr Light's research showing elevated fatigue and pain receptors after exertion?

Washington, D.C.-- On February 26, 2010, the Veterans Affairs Department announced that it will re-examine the disability claims of thousands of Persian Gulf War veterans still suffering from the mysterious Gulf War illnesses two decades after the war ended. At a meeting of the Federal Advisory Committee on Gulf War Veteran's Illnesses held yesterday in Washington, D.C., scientists from around the country presented their latest research to committee members searching for clues to this mysterious illness. Early in the meeting a new culprit emerged -- "the other brain" -- the non-electric portion of the brain composed of brain cells called glia.

"This is one of the best explanations I've heard," commented distinguished neuroscientist Floyd Bloom, after a presentation by Dr. Linda Watkins of the University of Colorado speaking about her latest research showing that glial cells, called microglia, are the unsuspected agents in chronic pain and drug addiction. Previously neurons were thought to be the sole cause of chronic pain and morphine tolerance. However, the new insight into how these "immune cells" of the brain aggravate neurons after an injury by releasing substances that produce excruciating pain, a parallel with Gulf War Syndrome became apparent.

Gulf War syndrome is characterized by a collection of unexplained symptoms, many of them neurological, including chronic pain, chronic fatigue, depression, sleep disturbances, memory loss, as well as gastrointestinal and lung problems. A number of causes have been suspected, including exposure to low-level neurotoxins, including sarin gas, drugs taken to protect soldiers from biological and chemical warfare agents, pesticides used to treat tents and soldier's uniforms stationed in the desert, depleted uranium from munitions, and the toxic mixture of fumes released for a year after the war ended from oil fields set ablaze by the retreating Iraq soldiers. The toxic fumes blotted out the sun at midday for miles.

Many people suffer chronic pain after an injury. Unlike normal pain, chronic pain does not end after the injury heals; in fact it often gets worse. The latest research shows that chronic pain results from an interaction between the immune system and the brain. When we are sick, substances are released by the body that tell the brain to initiate the familiar "sickness response," which we have all experienced, for example when we catch the flu. Profound fatigue, headache, sensitivity to light and sound, and painful joints and muscles, drive us to bed. This sickness response forces us to rest and give the body the opportunity to fight the invading germ. This sounds a lot like the symptoms of many Gulf War veterans.

What Dr. Watkins suspects, based on her research on microglia in chronic pain, is that an initial exposure to some toxin "primes" the microglia in the brain to make them hyper alert. Then when a second infection, injury, or toxin is experienced, the brain's immune cells over-react, releasing too much of the chemical signals that cause the "sickness response", and they do not stop releasing the substances after the body heals. In the case of Gulf War veterans, the "initial trigger" could have been a reaction to an immunization, stress, or exposure to low-level toxins. Later a second insult to the body unleashes a run-away illness. Research from several labs on microglia in chronic pain has identified many steps in this neuro-immune signaling process that become disrupted and researchers have found specific drugs to restore the normal function of these pain circuits, thus ending the chronic pain. Most of this work is in laboratory animals but clinical studies are now under way.

In my overview to the committee on the four major kinds of glial cells in "the other brain", several other ways in which glia could be involved in Gulf War illnesses were recognized. This includes the involvement of glial cells, called astrocytes, in processing toxins in the brain. Parkinson's disease, for example can be caused by astrocytes acting on a foreign substance (a recreational drug), and converting it into a toxin that kills the neurons that die in Parkinson's Disease. Astrocytes also release factors that protect neurons from damage caused by inflammation or oxidation, and they release growth factor proteins that stimulate the growth and repair of neurons.

The latest research on the myelin insulation on nerve fibers in the brain, which is essential for sending electrical signals, is revealing a previously unsuspected role of myelin in cognition and psychiatric illness. Myelin insulation is especially vulnerable to blast injuries and to autoimmune diseases in which the body's immune system attacks the myelin sheath. The myelin sheath is made by a type of glial cell, called an oligodendrocyte. Prevously this insulation was of interest in diseases such as multiple sclerosis, but because the insulation speeds the rate of electrical transmission through nerve fibers (axons), myelin is now understood to have an important role in cognitive function, psychological illness, and learning.

One of the reasons the Gulf War Syndrome may have been so difficult to understand is that glia--the other brain--has itself been such a mystery until recently.

Senior Member

It could, but the damaged microglia theory of CFS has been around before. Somebody will have to come up with a way to test and prove the hypothesis. Till then, it's just a theory along with a dozen others. My problem with microglia theory is that it does not explain dysautonomia and sex disparity in CFS population.

Senior Member

It could, but the damaged microglia theory of CFS has been around before. Somebody will have to come up with a way to test and prove the hypothesis. Till then, it's just a theory along with a dozen others. My problem with microglia theory is that it does not explain dysautonomia and sex disparity in CFS population.

This is new evidence, so probably some researcher will go back now and revisit the micoglia theory in a CFS context.

Just thinking about this, if microglia infection by something like HHV6 leads to a downstream depletion of glutathione, that might explain the gender differences given the higher hormone involvement (which must all be detoxified eventually by glutathione). And dysautonomia, hmm, maybe that depends on how/whether the infected microglia connect to the hypothalamus.

Microglia infection really is interesting since it can possibly explain the diverse sensory hyper-sensitivity in CFS. Also, if damaged microglia create an auto-stress situation, by the hypothesized secondary infection mentioned in that article, that would support the adrenal looping/depletion theory, which then creates all the other depletions we have in CFS.

ɹǝqɯǝɯ ɹoıuǝs

On occasion, the activation of microglia is not terminated and a state of chronic activation occurs. When this happens, significant damage can occur to a number of brain microstructures, especially synaptic connections and dendrites. While short term microglial activation can be neuroprotective (because of the secreted growth factors) chronic activation appears to be neurodegenerative. Newer studies have shown that chronic microglial activation occurs in a number of pathological states, including CNS trauma, infections, heavy metal toxicity, pesticide exposures. neurodegenerative diseases, autism, Downs syndrome and over-vaccination.

When microglia are activated, they also secrete two known excitotoxins-glutamate and quinolinic acid. In addition, they secrete a number of factors that are also known to enhance excitotoxicity, such as tumor necrosis factors-alpha (TNF-alpha), IL-1, IL-2, IL-4, IL-6 and IL-18, as well as interferons and other immune molecules. A number of studies have shown that several of these immune factors greatly enhance excitotoxicity, especially TNF-alpha and IL-1-two inflammatory cytokines that are elevated in all of the neurodegenerative diseases as well as autism.

Microglia also secrete a fatty molecule called arachidonic acid. This too enhances excitotoxicity. Arachidonic acid release increases the production of inflammatory eicosanoids, primarily by the action of LOX and COX enzymes. Studies have shown that glutamatergic neurons also contain COX enzymes and that excitotoxic destruction of neurons follows the presence of COX-2 enzymes. Blocking COX and LOX enzymes significantly reduces excitotoxicity. This accounts for some of the selectivity of excitotoxicity, that is, it will severely damage and/or kill some neurons and result in no harm to others close by.

Another damaging effect of chronic microglial activation, is a concept called by-stander damage. When the inflammatory cytokines, excitotoxins, eicosanoids, free radicals and lipid peroxidation products are released, they diffuse toward surrounding neurons and their dendrites and synapses. The longer the microglia are active, the greater and more widespread the damage becomes. So, why the selective damage?-that is, How can some neurons survive in such an environment? Studies have shown that neurons possessing strong antioxidant defenses, or lacking free radical-generative enzymes (such as NADPH oxidase) can escape the damage much longer than poorly protected cells and synaptic connections.

Likewise, glutamatergic neurons have been shown to contain COX-2 enzymes, whereas protected neurons do not. Blocking COX-2 has been shown to be neuroprotective in cases of excitotoxic activation, as mentioned. This explains the dramatic reduction in Alzheimers disease seen in epidemiologic studies in those who regularly take NSAIDS. Experimentally, NASIDS and other COX-2 and LOX blocking drugs and natural products can significantly attenuate excitotoxic damage.

In the excitotoxic cascade, PLA2 (phospholipase-A2) is activated by protein kinase-C, releasing arachidonic acid from the membrane of the neuron. LOX and COX enzymes convert arachidonic acid into leukotrienes and inflammatory prostaglandans, respectively. It is these eicosanoids that generate the reactive oxygen and reactive nitrogen species (peroxyl, superoxide and hydroxyl radicals) that ultimately damage the mitochondria, endoplasmic reticulum and nucleus during excitotoxic cascade activation.

During the opening of the calcium channel (in NMDA and AMPA glutamate receptors) the excess intracellular calcium also activates nitric oxide synthetase (NOS), which generates excessive amounts of nitric oxide (NO). The NO then reacts with superoxide to form peroxynitrite radical, which is a very powerful reactive nitrogen species (RNS). This RNS passes through the mitochondrial with great rapidity, and has been shown to be especially damaging to mitochondrial enzymes and mtDNA.

In essence, we see an interaction between eicosanoid production and nitric oxide production that ultimately results in a significant loss of mitochondrial energy production. A number of studies have shown that neuronal energy loss, no matter the cause, greatly increases neuronal, dendritic and synaptic sensitivity to excitotoxin damage.

In addition, some of the NSAIDS are known to be rather potent inhibitors of microglial activation. This is especially beneficial in cases of chronic microglial activation. It is also known that inhibition of microglial activation, once triggered, is dependent of certain cytokines, such as IL-10 and TGF-. Dysfunction in IL-10 activation, as seen with shifts from TH2 to Th1 cytokine activation, interfere with cessation of microglial activation. This switches microglia from a neuroprotective function to a neurotoxic one. In pathological states, such as Alzheimers dementia, Parkinsons disease and autism, it may be that a loss or dysfunction in brain growth factors also plays a role. This would make microglia a source of inflammatory cytokines, complement, S100B, eicosanoids, arachidonic acid and excitotoxins, without the protective factors.

Reduced levels or dysfunction of antioxidant enzymes, such as catalase, SOD, glutathione reductase, glutathione peroxidase and glutathione itself would also greatly increase neuronal sensitivity to excitotoxicity and free radical and lipid peroxidation damage.

As we have seen in my discussion of mercury toxicity, mercury not only is a powerful activator of microglial activity at micromolar or even submicromolar concentrations, but also at these same concentrations powerfully inhibits the glutamate transport proteins. At 0.5 uM we see a 50% reduction in glutamate uptake. The majority of extracellular glutamate is taken up by the astrocyte, which is the site of the greatest mercury accumulation in the CNS. The microglia is the second most abundant site of mercury accumulation.

Mercury also is a powerful inhibitor of glutamine synthase and glutamate dehydrogenase, both of which also play major roles in controlling extracellular glutamate levels. At lower concentrations of glutamate, glutamine synthase is the most important mechanism for astrocyte glutamate clearing. But at higher levels, glutamate dehydrogenase becomes more important.

So, we can see that a single heavy metal can powerfully interfere with glutamate clearance by a number of mechanisms, resulting in excitotoxicity. In addition, mercury is a powerful inhibitor of mitochondrial enzymes and interferes with mitochondrial membranes function, both of which reduce neuronal energy production, as well as energy production by astrocytes and microglia. This energy loss, as we have seen, magnifies excitotoxicity.

Mercury is not the only thing that can precipitate these chains of events. Pesticides, other heavy metals, elevated free radical presence, 4-hydroxynonenal, infectious organisms, glutamate itself, other excitotoxins and oxidized LDL-cholesterol in the brain can have the same effect. It is the synergistic effects of a number of environmental and metabolic toxins that, in my opinion, results in the neurodegenerative diseases, autism, Downs syndrome and a number of other neurological conditions. Yet, central to the process in all these conditions is chronic microglial activation.

Senior Member

Thank you for posting this Frickly! I want to mention that when I lived in Germany, there was a documentary on American Soldiers during the 2nd gulf war (I think it was in 2005). I wish I could find this on the internet and for the life of me, I can not remember the title. It was in German. Anyway, they showed a veteran that was damaged by vaccines he had to take before he went to serve. Please keep in mind that I am not one of those anti-vaccine people that shout and rage that vaccines do nothing but harm but I do think there may be a problem when given too many vaccines or in some cases, some people may have a genetic predisposition or some other environmental insult that sets their immune system over the top when given vaccines.

Another thing I want to mention, my father died of a glioblastoma (GLIAL CELLS) brain tumour in 1996. It was also during this time period that my sister-in-law and aunt came down with ME/CFS. My two children were born in 1998 and 2000 and have autism. Although my sister-in-law is not genetically related to me, I do wonder if XMRV plays havoc on people with a certain genetic predispostion. I also want to mention that my uncle's wife was also diagnosed with MS in 1996 and died in 2008.

Senior Member

I suspect that Gulf War Illness and CFS share glutathione depletion and a partial methylation cycle block. I attended two meetings of this committee in Washington, D.C. several years ago, and spoke to them as well as writing to them about this many times. I wasn't able to convince them. Also, I don't think this committee has the power to influence what the VA does. They can only give advice.

I also tried to convince some people who have GWI to try this approach, via one of the veterans' internet groups. I didn't have much luck there, either. Most of them seem to be waiting for the VA to do something for them, rather than being willing to try things themselves.

I really did want to help the veterans, being a Vietnam veteran myself, but just wasn't able to get very far. I may try writing to the committee again.

The mix of stressors that brought about the glutathione depletion initially was probably different in most GWI cases froim the stressors in most CFS cases, probably including the vaccinations and the chemical toxins to which the troops were exposed, as well as the stress of war.

It's true that the oligodendrocytes (one type of glial cell) form the myelin that serves as insulation around the nerve axons in the brain. I think that the link here is that methylation is required to make phosphatidyl choline from phosphatidyl ethanolamine, and it is also required to make myelin basic protein. Both are essential components of myelin. Without sufficient methylation capacity, the myelin probably degrades over time and is not properly repaired and maintained. The evidence for myelin problems in CFS is the observed low processing speed in the brain. The speed of transport of nerve impulses depends very much on the condition of the myelin.

Senior Member

I suspect that Gulf War Illness and CFS share glutathione depletion and a partial methylation cycle block. I attended two meetings of this committee in Washington, D.C. several years ago, and spoke to them as well as writing to them about this many times. I wasn't able to convince them. Also, I don't think this committee has the power to influence what the VA does. They can only give advice.

...

It's true that the oligodendrocytes (one type of glial cell) form the myelin that serves as insulation around the nerve axons in the brain. I think that the link here is that methylation is required to make phosphatidyl choline from phosphatidyl ethanolamine, and it is also required to make myelin basic protein. Both are essential components of myelin. Without sufficient methylation capacity, the myelin probably degrades over time and is not properly repaired and maintained. The evidence for myelin problems in CFS is the observed low processing speed in the brain. The speed of transport of nerve impulses depends very much on the condition of the myelin.

Rich, do you have a copy of any of your writing about this topic? How the glial cell problems might connect to CFS? Or maybe what you sent to that committe? I would love to read that.

Also, the idea of low processing speed being due to leakage, that is interesting. So we might have a short-circuit type problem. But one obvious problem with that idea is that some people do go into remission rapidly, and also the brain fog seems to wax and wane. Not what one would expect with permanent damage like that, or damage that is very slow to repair. Maybe the glial cell problems are yet another subset issue.

Researchers have found it hard to dig into the immune cells in the brain but this researcher thinks they play a key role in the
problems in GWS (and therefore CFS). GWS should be such a boon to us and I'm surprised we haven't followed it more closely. Dr. Klimas says its the same thing. Thistheory even incorporates the two-hit phennomena as well as hyper sensitization - and its all centered on immune cells in the brain - the micro-glia.

Washington, D.C.-- On February 26, 2010, the Veterans Affairs Department announced that it will re-examine the disability claims of thousands of Persian Gulf War veterans still suffering from the mysterious Gulf War illnesses two decades after the war ended. At a meeting of the Federal Advisory Committee on Gulf War Veteran's Illnesses held yesterday in Washington, D.C., scientists from around the country presented their latest research to committee members searching for clues to this mysterious illness. Early in the meeting a new culprit emerged -- "the other brain" -- the non-electric portion of the brain composed of brain cells called glia.

"This is one of the best explanations I've heard," commented distinguished neuroscientist Floyd Bloom, after a presentation by Dr. Linda Watkins of the University of Colorado speaking about her latest research showing that glial cells, called microglia, are the unsuspected agents in chronic pain and drug addiction. Previously neurons were thought to be the sole cause of chronic pain and morphine tolerance. However, the new insight into how these "immune cells" of the brain aggravate neurons after an injury by releasing substances that produce excruciating pain, a parallel with Gulf War Syndrome became apparent.

Gulf War syndrome is characterized by a collection of unexplained symptoms, many of them neurological, including chronic pain, chronic fatigue, depression, sleep disturbances, memory loss, as well as gastrointestinal and lung problems.[/I (sound familiar?)] A number of causes have been suspected, including exposure to low-level neurotoxins, including sarin gas, drugs taken to protect soldiers from biological and chemical warfare agents, pesticides used to treat tents and soldier's uniforms stationed in the desert, depleted uranium from munitions, and the toxic mixture of fumes released for a year after the war ended from oil fields set ablaze by the retreating Iraq soldiers. The toxic fumes blotted out the sun at midday for miles.

Many people suffer chronic pain after an injury. Unlike normal pain, chronic pain does not end after the injury heals; in fact it often gets worse. The latest research shows that chronic pain results from an interaction between the immune system and the brain. (substitute fatigue for pain here?)

When we are sick, substances are released by the body that tell the brain to initiate the familiar "sickness response," which we have all experienced, for example when we catch the flu. Profound fatigue, headache, sensitivity to light and sound, and painful joints and muscles, drive us to bed. This sickness response forces us to rest and give the body the opportunity to fight the invading germ. This sounds a lot like the symptoms of many Gulf War veterans.

(Sickness response - A key question in CFS as well)

What Dr. Watkins suspects, based on her research on microglia in chronic pain, is that an initial exposure to some toxin "primes" the microglia in the brain to make them hyper alert. Then when a second infection, injury, or toxin is experienced, the brain's immune cells over-react, releasing too much of the chemical signals that cause the "sickness response", and they do not stop releasing the substances after the body heals.

(This could be CFS right here: you could be looking at the cause of CFS right here)

In the case of Gulf War veterans, the "initial trigger" could have been a reaction to an immunization, stress, or exposure to low-level toxins. Later a second insult to the body unleashes a run-away illness.Research from several labs on microglia in chronic pain has identified many steps in this neuro-immune signaling process that become disrupted and researchers have found specific drugs to restore the normal function of these pain circuits, thus ending the chronic pain. Most of this work is in laboratory animals but clinical studies are now under way.

In my overview to the committee on the four major kinds of glial cells in "the other brain", several other ways in which glia could be involved in Gulf War illnesses were recognized. This includes the involvement of glial cells, called astrocytes, in processing toxins in the brain. Parkinson's disease, for example can be caused by astrocytes acting on a foreign substance (a recreational drug), and converting it into a toxin that kills the neurons that die in Parkinson's Disease. Astrocytes also release factors that protect neurons from damage caused by inflammation or oxidation, and they release growth factor proteins that stimulate the growth and repair of neurons.

The latest research on the myelin insulation on nerve fibers in the brain, which is essential for sending electrical signals, is revealing a previously unsuspected role of myelin in cognition and psychiatric illness. Myelin insulation is especially vulnerable to blast injuries and to autoimmune diseases in which the body's immune system attacks the myelin sheath. The myelin sheath is made by a type of glial cell, called an oligodendrocyte. Prevously this insulation was of interest in diseases such as multiple sclerosis, but because the insulation speeds the rate of electrical transmission through nerve fibers (axons), myelin is now understood to have an important role in cognitive function, psychological illness, and learning.

One of the reasons the Gulf War Syndrome may have been so difficult to understand is that glia--the other brain--has itself been such a mystery until recently.

* Chronic pain that persists after an injury heals is often caused by overly excited pain-sensing neurons that signal without an external stimulus.
* Traditional pain drugs that target neural cells directly rarely quiet these abnormal pain messages because the neurons' heightened sensitivity is driven by a different type of cell called glia.
* Such cells monitor the activity of neurons and attempt to keep them healthy and functioning efficiently. But well-intentioned glial reactions to intense pain can at times prolong that pain.

Gerwyn

Guest

Researchers have found it hard to dig into the immune cells in the brain but this researcher thinks they play a key role in the
problems in GWS (and therefore CFS). GWS should be such a boon to us and I'm surprised we haven't followed it more closely. Dr. Klimas says its the same thing. Thistheory even incorporates the two-hit phennomena as well as hyper sensitization - and its all centered on immune cells in the brain - the micro-glia.

Senior Member

Abstract
Many symptoms of chronic fatigue syndrome (CFS), including severity of fatigue, may be periodic, fluctuant and induced by physical and mental activities, including trauma and stress. The fatigue in CFS is distinct from the fatigue of neuromuscular disorders but is similar to that found in disorders of the central nervous system such as multiple sclerosis, Parkinson's disease and multiple system atrophy. Though fatigue is a common symptom of depressive disorders, it is now clear that CFS patients differ from patients with major depression in their symptoms, biologic markers such as steroid metabolism and response to standard antidepressant drug therapy. In this paper, we propose dysfunctional ion channels in the cell membranes as the key abnormality in CFS which may also be responsible for the altered neuroendocrine functions reported in this condition. In our hypothesis, changes in the neuronal ion channel function from time to time offers a rational basis to explain fluctuating fatigue and related symptoms in CFS. Finally, ion channel abnormality leading to selective neuronal instability may be the common disease mechanism in CFS and other paroxysmal disorders affecting brain functions such as migraine and epilepsy. Copyright 1999 John Wiley & Sons, Ltd. http://www3.interscience.wiley.com/journal/40002006/abstract?CRETRY=1&SRETRY=0

Yes, maybe start a forum on GWS, or just a long running robust thread on this forum about the similarities. I am particularly interested since I became ill while working at a hazardous waste disposal facility. Unfortunately, I suspect I might have been exposed to some of the same toxic chemicals to which military people have been exposed. Yuck.